Study On The 1,3-dipolar Cycloaddition Reaction Of Benzosultam-3-ylidenes

Benzosultams are important scaffolds in drug discovery due to their diverse pharmaceutical and biological activities. In this article, the 1,3-dipolar cycloadditon reaction of benzosultam-3-ylidenes with three kind of dipoles was studied and a series of spirobenzosultams and 3,4,5-trisubstituted isoxazole derivatives were synthesized.In the first section, the advances in 1,3-dipolar cycloadditon reactions including the classification of 1,3-dipoles, the mechanism of reaction, the classification of1,3-dipolar reaction and the application of three dipoles in recent organic synthesis were summarized. In addition, the applications of benzosultams in medicines,pesticides, and organic synthesis were introduced.In the second section, the new spiropyrrolidinyl-benzosultam derivatives were synthesized by the 1,3-dipolar cycloaddition of benzosultam-3-ylidenes and azomethine ylide. The stereochemistry of 1,3-dipolar cycloaddition as well as the stereochemistry of Knoevenagel condensation of benzoisothiazole-2,2-dioxide with aldehydes were studied. The effects of Lewis acid, solvents, and temperature on the reaction were studied. With optimized reaction conditions, we tested the scope of benzosultam-3-ylidenes in the cycloaddition and developed a synthetic method to spiropyrrolidinyl-benzosultam derivatives.In the third section, a straightforward synthesis of 3,4,5-trisubstituted isoxazole derivatives via 1,3-dipolar cycloaddtion/SO2 extrusion of benzosultam-3-ylidenes with nitrile oxides was reported using 4? molecular sieves as a dehydrochlorinating agent.The best results were obtained when reactions were carried out in toluene at 80℃,with 4? molecular sieves as the catalyst. This tandem ring closing/ring opening synthesis of 3,4,5-trisubstituted isoxazoles is the first of its kind. This methodology would enrich the synthetic chemistry of isoxazoles from easily available starting materials and benefit the discovery of novel isoxazoles with potential biological activities.In the fourth section, we explored an approach to synthesize a new kind ofspiroisoxazolinyl-benzosultam derivatives with high regioselectivity and diastereoselectivity. The substrate scope of nitrones and dipolarophiles were investigated and steric hindrance played an important role in the 1,3-dipolar cycloaddition. The relative stereochemistry in sprio products was studied and determined from the single-crystal X-ray crystallography in endoselective manner.In the fifth section, we discovered a AgOAc/(S,S)-ip-FOXAP-catalyzed asymmetric 1,3-dipolar cycloaddtion reaction of azomethine ylides with benzosultam-3-ethylidene. This highly regioselective and enantioselective synthesis gave access to spiropyrrolidinyl-benzosultam derivatives with an all-carbon quaternary spirocentre and three tertiary centres in one step. The absolute configuration of the cycloadduct was unambiguously determined by X-ray analysis and the stereochemical results of this annulation could be explained through the proposed transition state.The structures of compounds were characterized by 1H NMR, 13 C NMR, and HRMS. Furthermore, the stereochemistry of the adduct 7d, 7f, 7g, 10 e, 12 a and 16 e were assigned by X-ray crystallography analysis, and the stereochemistry of the other products were assigned by analogy.